DESCRIPTION (Applicant's Abstract) There is evolving evidence that circulating blood contains active tissue factor (TF) and that this may lead to enhanced blood thrombogenicity. Risk factors for atherosclerotic disease, such as hypercholesterolemia, cigarette smoking, and diabetes type 2 may in part act as triggers of enhanced blood thrombogenicity. In about a third of acute coronary syndromes (ACS) there is not the usual disruption of a small lipid-rich plaque but just a superficial erosion of a stenotic and fibrotic plaque (Fig 1). Thus, complicated thrombi in such cases may well be the result of an increased blood thrombogenicity- TF dependent, triggered by systemic risk factors such as those mentioned above. We will test the hypothesis that enhanced blood thrombogenicity and circulating tissue factor (TF) activity will be found in individuals with hypercholesterolemia, with diabetes type 2 and in cigarette smokers (AIM 1a); decreased thrombogenicity and normalization of circulating TF activity will be obtained with risk factor modifying approaches (AIM 1b). In two cohorts of patients with atherosclerotic disease and hypercholesterolemia, changes in circulating TF activity will be correlated with modification of hypercholesterolemia and with primary efficacy as measured by the rate of plaque regression/stabilization/progression by noninvasive magnetic resonance imaging (MRI) of the carotid arteries, thoracic aorta and coronary arteries in one cohort (AIM 2a) and by invasive coronary intravascular ultrasound (IVUS)in the other cohort (AIM 2b). Finally, in the ongoing women's Health Study, the relationship between circulating TF activity and cardiovascular events will be approached (AIM 3a), as well as the relationship between these two parameters and the presence of hypercholesterolemia, diabetes type 2 or cigarette smoking (AIM 3b). Platelet - leukocyte aggregates and activation in blood and C-reactive protein (CRP) in plasma will also be measured as part of the various aims.